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HUE026917T2 - Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates - Google Patents

Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates Download PDF

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HUE026917T2
HUE026917T2 HUE07766518A HUE07766518A HUE026917T2 HU E026917 T2 HUE026917 T2 HU E026917T2 HU E07766518 A HUE07766518 A HU E07766518A HU E07766518 A HUE07766518 A HU E07766518A HU E026917 T2 HUE026917 T2 HU E026917T2
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salt
acid
carbamoylmethyl
methylhexanoic acid
amine
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HUE07766518A
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Hungarian (hu)
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Annibale Salvi
Antonio Nardi
Angelis Bruno De
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Laboratorio Chimico Int S P A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/20—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

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  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Description
SUMMARY OF THE INVENTION
[0001] The present invention relates to the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, in particularthe resolution of the acid racemate by means of salification with optically active amines and the isolation of the (R) enantiomer of the acid. This invention also relates to the intermediate salts formed with said amines and the conversion of said (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid into biologically active molecules such as pregabalin.
TECHNICAL BACKGROUND
[0002] The separation of enantiomers by means of salification with appropriate optically active counter-ions has been known for some time. However, the selection of the most suitable counter-ion and the reaction conditions, particularly the solvent and the temperature, allowing the attainment of good separation through the precipitation of one of the two diastereoisomeric salts, are difficult to predict.
[0003] (R)-(-)-3-(carbamoylmethyl)-5-methylhexano-ic acid is an intermediate, useful in the preparation of biologically active molecules, such as for example pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid).
[0004] W001/40159 discloses the resolution of phenyl-propanoic acids by reaction with chiral amines, i.a.
[5] -(-)-1 -(1 -naphthyl)-ethylamine.
[0005] XP-002459064 (JP20030032863-abstract) discloses the resolution of chlorocyclopropan-carboxilic acid using an optically active amine, i.a. (R)-phenyl-glycinol.
[0006] EP0828704 describes the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid by means of the salification of the acid racemate with (R)-(+)-a-phenylethylamine in chloroform, precipitation following cooling and subsequent acid hydrolysis of the salt formed between the R enantiomer of the acid and the optically active amine. The text of the patent indicates generically that the salification reaction/precipitation may proceed in an "organic solvent" but the examples normally report the use of chloroform, with the addition of a little ethanol. As is well known, chloroform is a solvent that cannot be used industrially since it is carcinogenic, even simply by inhalation.
Attempts to reproduce the described separation in a solvent other than chloroform have given negative results. In particular, crystallisation/precipitation has been attempted in solvents more suited to industrial use, such as ethyl acetate, cyclohexane, methanol, isopropanol, toluene, acetone, tetrahydrofuran and mixtures thereof, without attaining effective enantiomeric separation.
[0007] Hence, there remains a need to discover alternative synthetic pathways for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid.
DESCRIPTION OF THE INVENTION
[0008] It has now been found out that (R)-(-)-3-(car-bamoylmethyl)-5-methylhexanoic acid can be obtained through the salification of 3-(carbamoylmethyl)-5-meth-ylhexanoic acid racemate with an optically active amine suitable for enantiomeric separation selected from 1-(1-naphthyl)ethylamine and phenylglycinol in optically active form. Indeed, it has been found thatsuch amines arc particularly effective in the separation of the above-mentioned diastereoisomeric salts. There have been many attempts using different amines, but in the majority of cases the results have been somewhat disappointing.
[0009] Thus, according to one of the aspects thereof, the subject-matter of the present invention is a process for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, comprising reacting 3-(carbamoyl-methyl)-5-methylhexanoic acid racemate with an amine selected from 1-(1-naphthyl)ethylamine and phenylglycinol, in optically active form, in a solvent selected from ethyl acetate alcohols, dioxane and mixtures thereof, separating the two diastereoisomeric salts and recovering the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid from the corresponding salt.
[0010] 3-(carbamoylmethyl)-5-methylhexanoic acid has the following formula (I)
(I) where the asterisk indicates the chiral carbon atom.
[0011] Phenylglycinol has the following formula (II)
(II) where the asterisk indicates the chiral carbon atom.
[0012] 1-(1-naphthyl)ethylamine has the following formula (III)
(Ill) where the asterisk indicates the chiral carbon atom.
[0013] The above-indicated amines, in both (S) and (R) optically active forms, may be used for the separation of the desired enantiomer of the acid.
[0014] Unless expressly indicated otherwise, in the present description, the term "amine", used in relation to the process of the invention, refers to one of the above-indicated amines in ((S) or (R)) optically active form.
[0015] Furthermore, it has surprisingly been found that, independently of the 1-(1-naphthyl)ethylamine enantiomer used, the least soluble salt, i.e. the one which precipitates, is always that of the (S)-(+) enantiomer of the acid, i.e. the undesired enantiomer according to the present invention.
[0016] Thus, according to a first embodiment, the subject-matter of the present invention is a process for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhcx-anoic acid, comprising reacting 3-(carbamoylmethyl)-5-methylhexanoic acid racemate with an amine selected from (S)-(+)-phenylglycinol and 1 -(1 -naphthyljethyl-amine, the latter in any optically active form, in a solvent as above defined, precipitating and removing the precipitate consisting of the salt of the (S)-(+) enantiomer of the acid, and recovering (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid from the mother liquor. According to a second embodiment, the subject-matter of the present invention is a process for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid comprising reacting 3-(carbamoylmethyl)-5-methylhex-anoic acid racemate with (R)-(-)-phenylglycinol in a solvent as above defined; recovering the precipitate consisting of the salt with the (R)-(-) enantiomer of the acid; and isolating (R)-(-)-3-(carbamoylmethyl)-5-methylhex-anoic acid.
[0017] Thus, alternatively, an amine selected from (R)-(+)-1-(1-naphthyl)ethyl amine, (S)-(-)-1 -(-naph-thyljethylamine, (S)-(+)-phenylglycinol and (R)-(-)-phe-nylglycinol may be used for the process of the present invention.
[0018] The amines (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(+)-phenylglycinol are the preferred amines according to the invention.
[0019] Any solvent allowing the separation of the two enantiomers of the acid, by fractional crystallisation of the diastereoisomeric salts, may be used.
[0020] According to the invention, the solvent is an industrially acceptable solvent.
[0021] According to the present invention, by the term "industrially acceptable solvent" is meant any solvent which is not advised against for industrial use, for example, a solvent selected from ethyl acetate, alcohols such as methanol, ethanol, isopropanol, dioxane and the like, and mixtures thereof.
[0022] The selected amine is preferably used to salify at least 60% of the acid racemate used, i.e. in an amine/acid molar ratio equal to at least 0.6/1.
[0023] The quantity of solvent, or mixture of solvents, used in the initial salification is preferably comprised of between 7 and 9 ml per g of acid racemate.
[0024] The salification reaction occurs at a temperature comprised of between 25°C and the reaction mixture reflux temperature, preferably between 50°C and 70°C for example, at around 65-70 °C.
[0025] According to the first embodiment of the invention, the salt of the (S)-(+) enantiomer of the acid may be precipitated and removed from the mother liquor in accordance with known methods, for example by cooling and filtration.
[0026] Thus, in order to precipitate the salt of the undesired enantiomer, once the acid and the selected amine are dissolved in the solvent, the reaction mixture is cooled, for example to a temperature of approx. 10°C or less, and the precipitating salt of the amine with the (S)-(+) enantiomer of the acid may be removed by filtration, thereby separating it from the salt of the (R) enantiomer, which remains in solution.
[0027] Once the salt of the undesired enantiomer is removed, the (R)-(-)-3-(carbamoylmethyl)-5-methylhex-anoic acid salt with the amine may be recovered from the mother liquor according to conventional techniques known to those skilled in the art.
[0028] For example, the salt may be isolated so as to then liberate the free acid in accordance with known methods.
[0029] Alternatively, and according to a first preferred embodiment of the invention, the acid may be isolated from the mother liquor by extraction with water and alkali; so that the optically active amine remains in solution and the acid is extracted in a differently salified form.
[0030] Thus, according to the above-indicated first preferred embodiment, after the precipitation and removal of the salt of the undesired enantiomer, the (R)-(-) enantiomer of the acid can be recovered from the salification mother liquor by extraction with water and alkali, for example by extraction with an aqueous solution of an alkaline hydroxide, for example sodium hydroxide. The salt of the desired enantiomer of the acid with the alkaline metal in solution may then be isolated by concentration of the solution under reduced pressure. Alternatively, the free acid form of the desired enantiomer may be obtained by acidification of the alkaline solution, and filtration of the precipitate thus obtained.
[0031] According to the second embodiment, i.e. when (R)-(-)-phenylglycinol is used as the amine, the salt which precipitates is directly the desired salt, which can be isolated, for example by filtration, and from which (R)-(-)- 3-(carbamoylmethyl)-5-methylhexanoic acid can be liberated according to methods known to those skilled in the art.
[0032] (R)-(-)-3-(carbamoylmethyl)-5-methylhexano-ic acid may optionally be purified according to conventional techniques, for example, crystallisation in a suitable solvent.
[0033] The undesired enantiomer for pregabalin preparation may be "racemised" according to known techniques and reused according to the process of the present invention. The examples provided in the experimental section of the present description illustrate the process of the invention in detail.
[0034] The (S)-(+)-phenylglycinol salt of (R)-(-)-3-(car-bamoylmethyl)-5-methylhexanoic acid and the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylme-thyl)-5-methylhexanoic acid represent another subject-matter of the present invention.
[0035] The (R)-(-)-phenylglycinol salt of (R)-(-)-3-(car-bamoylmethyl)-5-methylhexanoic acid and the (R)-(-)-phenylglycinol salt of (S)-(+)-3-(carbamoylme-thyl)-5-methylhexanoic acid represent another subject-matter of the present invention.
[0036] The (R)-(+)-1-(1-naphthyl)ethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and the (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid represent another subject-matter of the present invention.
[0037] The (S)-(-)-1-(1-naphthyl)ethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and the (S)-(-)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid represent another subject-matter of the present invention.
[0038] As already mentioned, (R)-(-)-3-(carbamoylme-thyl)-5-methylhexanoicacid is an intermediate, useful for the preparation of biologically active molecules, and for example may be converted into pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid) through a Hoffman degradation, well known to those skilled in the art.
[0039] Thus, according to another aspect thereof, another subject-matter of the invention is a process for the preparation of pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid) comprising a) reacting 3-(carbamoylmethyl)-5-methylhexanoic acid racemate in a solvent with an amine selected from 1-(1-naphthyl)ethylamine and phenylglycinol, in optically active form; b) separating the two diastereoisomeric salts and recovering the (R)-(-)-3-(carbamoylmethyl)-5-meth-ylhexanoic acid from the corresponding salt; c) optional purifying the (R)-(-)-3-(carbamoylme-thyl)-5-methylhexanoic acid by crystallisation from an organic solvent; d) optional converting the (R)-(-)-3-(carbamoylme-thyl)-5-methylhexanoic acid into pregabalin.
[0040] The above-indicated steps (a) to (d) are prefer ably carried out according to the previously indicated methods.
[0041] The conversion of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid into pregabalin may be achieved for example by means of a Hoffmann degradation, according to reactions known to those skilled in the art.
[0042] The following examples illustrate the invention without limiting it in any manner.
Example 1
Preparation of the (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid.
[0043] 10 g (53.4 mmoles) of 3-(carbamoylmethyl)-5-methylhexanoic acid racemate are added to a mixture of ethyl acetate (60 ml) and methanol (8 ml) at 25°C. 8.8 g (51.4 mmoles) of (R)-(+)-1-(1-naphthyl)ethylamine are added dropwise over 10 minutes in order to obtain complete dissolution. The solution is heated at reflux temperature (68°C). The mixture is cooled slowly to 10°C to obtain the crystallisation of the salt. The solid is filtered and washed with 30 ml of ethyl acetate. The wet product is dried at 40°C for 6 hours giving 8 g of the (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylme-thyl)-5-methy Ihexanoic acid as a white sol id. The filtration mother liquor (approx. 80 ml) is used to obtain the desired (R)-(-)-3-( carbamoylmethyl)-5-methylhexanoic acid enantiomer.
Example 2
Preparation of (R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid.
[0044] The mother liquor (approx. 80 ml) obtained from the filtration of the (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid is extracted with an aqueous solution of sodium hydroxide (4.6 g of 30% sodium hydroxide diluted with 60 ml of water). The alkaline aqueous phase is further washed with 25 ml of ethyl acetate. The combined organic phases are stored (approx. 100 ml) for later recovery of the chiral amine (see example 5). The alkaline aqueous phase is concentrated under reduced pressure to give a weight of 60-65 g and then heated to 60°C. 4.3 g (39 mmoles) of 33% hydrochloric acid are added dropwise over 10 minutes to give a pH of 1 -1.5. The solution is cooled slowly to 20-25°C in order to obtain the precipitation of the crude (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The solid is filtered, washed with water and dried under reduced pressure at 50°C for 6 hours. The solid obtained (4.5 g) is then dissolved in 54 ml of ethyl acetate at reflux temperature (76°C); the hot solution is then filtered and cooled slowly to 25°C.
[0045] The solid precipitate is filtered and washed with 10 ml of ethyl acetate. After drying under reduced pressure at 40°C for 6 hours, 3.2 g of (R)-(-)-3-(carbamoyl- methyl)-5-methylhexanoic acid are obtained with a melting point of 132-135°C.
[a]D = -0.5 (C=2, methanol) 1H-NMR (CDCI3, 300 MHz): 0=0.93 (6H, d); δ=1.28 (2H, m); δ=1.7 (1H, m); 0=2.2-2.5 (5H, m); δ=5.7 (1H, bs); δ=6.3 (1H, bs).
Enantiomeric purity: e.e.>99% (DSC)
Example 3
Preparation of the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid.
[0046] 10 g (53,4 mmoles) of 3-(carbamoylmethyl)-5-methylhexanoic acid racemate are added to a mixture of ethyl acetate (60 ml) and methanol (29 ml) at 25°C. 6.6 g (48.1 mmoles) of (S)-(+)-phenylglycinol are added and the mixture heated to reflux temperature (68°C) to obtain complete dissolution. The mixture is cooled slowly to 25°C to obtain the crystallisation of the salt. The solid is filtered and washed with 30 ml of ethyl acetate. The wet product is dried at 40°C for 6 hours giving 6.1 g of the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylme-thyl)-5-methylhexanoicacid as a white solid. The filtration mother liquor (approx. 80 ml) is used to obtain the desired (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid enantiomer.
Example 4
Preparation of (R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid.
[0047] The mother liquor (approx. 80 ml) obtained from the filtration of the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoicacid is extracted with an aqueous solution of sodium hydroxide (4.5 g of 30% sodium hydroxide diluted with 60 ml of water). The alkaline aqueous phase is further washed with 30 ml of ethyl acetate. The alkaline aqueous phase is concentrated under reduced pressure to give a weight of 60-65 g and then heated to 60°C. 5 g (39 mmoles) of 33% hydrochloric acid are added dropwise over 10 minutes to give a pH of 1-1.5. The solution is cooled slowly to 20-25°C in order to obtain the precipitation of the crude (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The solid is filtered, washed with water and dried under reduced pressure at 50°C for 6 hours. The solid obtained (5 g) is then dissolved in 25 ml of ethyl acetate and 5 ml of methanol at reflux temperature (67°C); the hot solution is then filtered and cooled slowly to 25°C. The solid precipitate is filtered and washed with 10 ml of ethyl acetate. After drying under reduced pressure at 40°C for 6 hours, 2.5 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid are obtained with a melting point of 132-135°C.
[«]□ = -0.5 (C=2, methanol) enantiomeric purity: e.e.>99% (DSC)
Example 5
Preparation of the (S)-(+)-phenylglycinol salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid.
[0048] The mother liquor (approx. 80 ml) obtained from the filtration of the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid of Example 3 is concentrated to approx. 1Λ of the initial volume by distillation of the solvent at atmospheric pressure. The solution is progressively cooled to 25°C; the solid is filtered and washed with 20 ml of ethyl acetate and subsequently dried at 40°Cfor6 hours. 7 g of the (S)-(+)-phe-nylglycinol salt of (R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid are obtained as a white solid.
Example 6
Recovery of (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid.
[0049] From examples 1 and 2 it is possible to recover the following products: • 8 g of the (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid. • the combined organic phases (approx. 100 ml) • the crude (R)-(-)-3-(carbamoylmethyl)-5-methylhex-anoic acid precipitation mother liquor (aqueous acid solution) • the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid crystallisation mother liquor (approx 70 ml) and these are combined in a reaction flask.
[0050] To the mixture obtained is added 30% aqueous sodium hydroxide until the pH is >10. The two clear phases thus obtained are separated. The organic phase is filtered and evaporated to residue to give 7.5 g of recovered (R)-(+)-1-(1-naphthyl)ethylamine which can be used in the subsequent preparation. The alkaline aqueous phase is acidified with hydrochloric acid and gives a precipitate which is filtered and dried at 50°C under reduced pressure. 5 g of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid are thus obtained which can be "ra-cemised" by acid hydrolysis to give 3-isobutyl glutaric acid. 3-isobutyl glutaric acid is the precursor of 3-(car-bamoylmethyl)-5-methylhexanoic acid racemate.
Example 7 [0051] The salts of the enantiomers of 3-(carbamoyl-methyl)-5-methylhexanoic acid with optically active amines have the following characteristics. (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoyl-methyl)-5-methylhexanoic acid Melting point (DSC) = 160-164°C; [α]ο20= +11.7 (C=1, methanol) (S)-(+)-phenylglycinol salt of (R)-(-)-3-(carbamoyl-methyl)-5-methylhexanoic acid Melting point (DSC) = 129-133°C; [a]o20= +19.4 (C=1, methanol) (R)-(-)-phenylglycinol salt of (S)-(+)-3-(carbamoyl-methyl)-5-methylhexanoic acid Melting point (DSC) = 129-133X; [a]D20= -19.3 (C=1, methanol) (R)-(-)-phenylglycinol salt of (R)-(-)-3-(carbamoyl-methyl)-5-methylhexanoic acid Melting point (DSC) = 160-164°C; [a]D20= -11.5 (C=1, methanol)
The (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid. Melting point (DSC) = 158-162°C; [a]D20= +3.5 (C=1, methanol) (R) -(+)-1-(1-naphthyl)ethylamine sa|t 0f (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. Melting point (DSC) = 120-124X; [a]020= +11.6 (C=1, methanol) (S) -(-)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid. Melting point (DSC) = 120-124°C; [«]d20=-11.1 (C=1, methanol) (S)-(-)-1-(1-naphthyl)ethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. Melting point (DSC) = 158-162°C; [a]o20= -3.2 (C=1, methanol)
Example 8
Preparation of the (R)-(-)-phenylglycinol salt of(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid in 1,4-diox-ane.
[0052] 8 g (42.8 mmoles) of 3-(carbamoylmethyl)-5- methylhexanoic acid racemate are added to 30 ml of 1,4-dioxane at 25°C. The suspension is heated at 70°C in order to obtain complete dissolution. Separately, a solution of 4 g (29.2 mmoles) of (R)-(-)-phenylglycinol in 50 ml of 1,4-dioxane is prepared at 70°C, which is then added dropwise to the reaction flask over approx. 10 minutes, while maintaining the temperature at 70-75°C. The mixture is heated at 90°C until complete solution is obtained. The mixture is cooled slowly to 70°C to obtain the crystallisation of the salt. The solid is filtered at 65-70°C and washed with 10 ml of 1,4-dioxane. The wet product is dried at 40°C for 6 hours giving 4.4 g of the (R)-(-)-phe-nylglycinol salt of (R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid as a white solid with a melting point between 158 and 161°C.
Example 9
Preparation of (R)-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid.
[0053] 4.4 g (13.6 mmoles) of the (R)-(-)-phenylglyci-nol salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexano-ic acid, obtained in Example 8, are loaded into 18 ml of water. The suspension is heated at 60°C in order to obtain complete dissolution. 1.9 g of 33% aqueous hydrochloric acid are added dropwise while maintaining the temperature at 60-62°C. The mixture is cooled slowly to 25°C and then maintained at this temperature for 30 minutes. The solid is filtered and washed with 4 ml of water. The wet product is dried at 40°C for 6 hours to give 2.2 g of crude (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The solid obtained is then dissolved in 27 ml of ethyl acetate at reflux temperature; the hot solution is filtered and then cooled slowly to 25°C. The solid precipitate is filtered and washed with 5 ml of ethyl acetate. After drying under reduced pressure at 40°C for 6 hours, 1.9 g of (R) -(-)-3-(carbamoylmethyl)-5-methylhexanoic acid are obtained with a melting point of 132-135°C. Enantiomeric purity: e.e>99%.
Example 10
Preparation of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) [0054] 9.3 g (49.7 mmoles) of (R)-(-)-3-(carbamoylme-thyl)-5-methylhexanoic acid are dissolved in 15.6 g of a 15% aqueous solution of sodium hydroxide at a temperature of 5°C (solution A). A solution of 34.3 g (60.8 mmoles) of 13% sodium hypochlorite is prepared in 11.5 g of 30% aqueous sodium hydroxide (solution B). Solution B is added dropwise into solution A over 15 minutes, while maintaining the temperature below 20°C. Upon completion of addition the temperature of the mixture rises spontaneously up to 40-45°C. After 1 hour following addition, it is cooled to 5-10°C, and 16 g of 33% hydrochloric acid added slowly until pH 5 is reached. After stirring for 30 minutes at 5-10°C the white solid is filtered and washed with cold water. The wet product is dried at 50°C under reduced pressure for 6 hours. 5.7 g of crude (S) -(+)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) are isolated and purified by crystallisation from a mixture of 19 g of isopropyl alcohol and 19 g of water. 4.8 g of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) are thus obtained with a melting point of 192-196°C.
[α]ο = +10.7 (C=2, water) 1H-NMR (D20 300 MHz): 0=0.85 (3H, d); 0=0.87 (3H, d); 0=1.19 (2H, m); 0=1.63 (1H, m); 0=2-2.4 (3H, m); 0=2.86-3.04 (2H, m)
Enantiomeric purity: e.e>99% (HPLC)
Claims 1. A process for the preparation of (R)-(-)-3-(car-bamoylmethyl)-5-methylhexanoic acid, comprising reacting 3-(carbamoylmethyl)-5-methylhexanoic acid racemate with an amine selected from 1-(1-naph-thyl)ethylamine and phenylglycinol, in optically active form, in a solvent selected from ethyl acetate, alcohols, dioxane and mixtures thereof, separating the two diastereoisomeric salts and recovering the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid from the corresponding salt. 2. The process according to claim 1, characterised in that said solvent is dioxane. 3. The process according to any of the preceding claims, characterised in that said amine is used in an amine/acid molar ratio of at least 0.6/1. 4. The process according to claims 1 to 3, comprising reacting, in a solvent, 3-(carbamoylmethyl)-5-meth-ylhexanoic acid racemate with an amine selected from (S)-(+)-phenylglycinol and 1-(1-naphthyl)ethyl-amine, the latter being in any optically active form; precipitating and removing the precipitate represented by the salt of the (S)-(+) enantiomer of the acid; and recovering (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid from the mother liquor. 5. The process according to claim 4, characterised in that the salification reaction occurs at a temperature comprised of between 25°C and the reflux temperature of the reaction mixture. 6. The process according to any of claims 4 or 5, characterised in that said amine is selected from (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(+)-phenylglyci-nol. 7. The process according to any of claims 4 to 6, characterised in that (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is recovered from the mother liquor by extraction with an alkaline aqueous solution and subsequent acidification of said alkaline solution. 8. The process according to claim 7, characterised in that (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is isolated by filtration following acidification. 9. The process according to claims 1 to 3, comprising reacting 3-(carbamoylmethyl)-5-methylhexanoic acid racemate with (R)-(-)-phenylglycinol in a solvent; recovering the precipitate consisting of the salt with the (R)-(-) enantiomer of the acid; and isolating (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. 10. A compound selected from the group consisting of (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoyl-methyl)-5-methylhexanoic acid; (S)-(+)-phenylglyci-nolsaltof(R)-(-)-3-(carbamoylmethyl)-5-methylhex-anoic acid; R)-(-)-phenylglycinol salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid and (R)-(-)-phenylglycinol salt of (R)-(-)-3-(carbamoyl-methyl)-5-methylhexanoic, acid. 11. A compound selected from the group consisting of (R)-(+)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid; (R) -(+)-1-(1-naphthyl)ethylamine salt of (R)-(-)- 3-(carbamoylmethyl)-5-methylhexanoic acid; (S) -(-)-1-(1-naphthyl)ethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid and (S)-(-)-1-(1-naphthyl)ethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. 12. A process for the preparation of pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid) comprising: a) reacting 3-(carbamoylmethyl)-5-methylhexa-noic acid racemate in a solvent with an amine selected from 1-(1-naphthyl)ethylamine and phenylglycinol, in optically active form, said solvent being selected from ethyl acetate, alcohols, dioxane and mixtures thereof; b) separating the two diastereoisomeric salts and recovering the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid from the corresponding salt; c) optional purifying the (R)-(-)-3-(carbamoyl-methyl)-5-methylhexanoic acid by crystallisation from an organic solvent; d) converting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid into pregabalin. 13. The process according to claim 12, characterised in that in step (d) the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is converted into pregabalin by means of a Hoffmann degradation.
Patentansprüche 1. Ein Verfahren zur Herstellung von (R)-(-)-3-(Carba-moylmethyl)-5-methylhexansäure, enthaltend die Reaktion von 3-(Carbamoylmethyl)-5-methylhexan-säure-Racemat mit einem Amin ausgewählt aus 1-(1-Naphthyl)ethylamin und Phenylglycinol (2-Ami-no-2-phenylethanol), in einer optisch aktiven Form, in einem Lösungsmittel ausgewählt aus Ethylacetat, Alkoholen, Dioxanen und Mischungen davon, Trennen der zwei diastereoisomeren Salze und Gewinnen der (R)-(-)-3-(Carbamoylmethyl)-5-methylhe-xansäure aus dem entsprechenden Salz. 2. Das Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, dass das Lösungsmittel Dioxan ist. 3. Das Verfahren gemäß irgendeinem der vorherigen Ansprüche, dadurch gekennzeichnet, dass das
Amin in einem molaren Verhältnis von Amin/Säure von mindestens 0,6/1 verwendet wird. 4. Das Verfahren gemäß den Ansprüchen 1 bis 3, enthaltend die Reaktion, in einem Lösungsmittel, von 3-(Carbamoylmethyl)-5-methylhexansäure-Race-mat mit einem Amin ausgewählt aus (S)-(+)-Phenyl-glycinol und 1-(1-Naphthyl)ethylamin, wobei letztere in irgendeiner optisch aktiven Form vorliegen; Präzipitation und Entfernen des Präzipitats, das von dem Salz des (S)-(+)-Enantiomers der Säure dargestellt wird; und Gewinnen der (R)-(-)-3-(Carbamoyl-methyl)-5-methylhexansäure aus der Mutterlauge. 5. Das Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Salzbildungsreaktion bei einerTemperaturzwischen25°C undderRefluxtem-peratur der Reaktionsmischung erfolgt. 6. Das Verfahren gemäß irgendeinem der Ansprüche 4oder5, dadurch gekennzeichnet, dass das Amin ausgewählt ist aus (R)-(+)-1-(1-Naphthyl)ethylamin und (S)-(+)-Phenylglycinol. 7. Das Verfahren gemäß irgendeinem der Ansprüche 4 bis 6, dadurch gekennzeichnet, dass (R)-(-)-3-(Carbamoylmethyl)-5-methylhexansäure durch Extraktion mit einer alkalischen wässrigen Lösung und anschließender Ansäuerung der alkalischen Lösung aus der Mutterlauge gewonnen wird. 8. Das Verfahren gemäß Anspruch 7, dadurch gekennzeichnet, dass (R)-(-)-3-(Carbamoylmethyl)-5-methylhexansäure nach der Ansäuerung durch Filtrierung isoliert wird. 9. Das Verfahren gemäß den Ansprüchen 1 bis 3, enthaltend die Reaktion von 3-(Carbamoylmethyl)-5-methylhexansäure-Racemat mit (R)-(-)-Phenylgly-cinol in einem Lösungsmittel; Gewinnen des Präzipitats bestehend aus dem Salz mit dem (R)-(-)-En-antiomer der Säure; und Isolieren der (R)-(-)-3-(Car-bamoylmethyl)-5-methylhexansäure. 10. Eine Verbindung ausgewählt aus der Gruppe bestehend aus (S)-(+)-Phenylglycinol-Salz der (S)-(+)-3-(Carbamoylmethyl)-5-methylhexansäure, (S)-(+)-Phenylglycinol-Salz der (R)-(-)-3-(Carbamo-ylmethyl)-5-methylhexansäure, (R)-(-)-Phenylglyci-nol-Salz der (S)-(+)-3-(Carbamoylmethyl)-5-methyl-hexansäure und dem (R)-(-)-Phenylglycinol-Salz der (R)-(-)-3-(Carbamoylmethyl)-5-methylhexan-säure. 11. Eine Verbindung ausgewählt aus der Gruppe bestehend aus (R)-(+)-1-(1-Naphthyl)ethylamin-Salz der (S)-(+)-3-(Carbamoylmethyl)-5-methylhexansäure, (R)-(+)-1-(1-Naphthyl)ethylamin-Salz der (R)-(-)-3-(Carbamoylmethyl)-5-methylhexansäure, (S)-(-)-1-(1-Naphthyl)ethylamin-Salz der (S)-(+)-3-(Carba-moylmethyl)-5-methylhexansäure und (S)-(-)-1-(1-Naphthyl)ethylamin-Salz der (R)-(-)-3-(Carbamoyl-methyl)-5-methylhexansäure. 12. Ein Verfahren zur Fierstellung von Pregabalin ((S)-(+)-3-(Aminomethyl)-5-methylhexansäure) enthaltend: a) Reaktion von 3-(Carbamoylmethyl)-5-me-thylhexansäure-Racemat in einem Lösungsmittel mit einem Amin ausgewählt aus 1-(1-Naph-thyl)ethylamin und Phenylglycinol, in einer optisch aktiven Form, wobei das Lösungsmittel ausgewählt ist aus Ethylacetat, Alkoholen, Dioxanen und Mischungen davon; b) Trennen der zwei diastereoisomeren Salze und Gewinnen der (R)-(-)-3-(Carbamoylme-thyl)-5-methylhexansäure aus dem entsprechenden Salz; c) optional, Aufreinigen der (R)-(-)-3-(Carbamo-ylmethyl)-5-methylhexansäure durch Kristallisation aus einem organischen Lösungsmittel; d) optional, Umsetzung der(R)-(-)-3-(Carbamo-ylmethyl)-5-methylhexansäure zu Pregabalin. 13. Das Verfahren gemäß Anspruch 12, dadurch gekennzeichnet, dass in Schritt (d) die (R)-(-)-3-(Car-bamoylmethyl)-5-methylhexansäure mittels des Floff-mann-Umbaus zu Pregabalin umgesetzt wird.
Revendications 1. Procédé de préparation d’acide (R)-(-)3-(carbamoyl-méthyl)-5-méthylhexanoïque, comprenant la mise en réaction d’un racémate d’acide 3-(carbamoylmé-thyl)-5-méthylhexanoïque avec une amine choisie parmi la 1-(1-naphtyl)éthylamine et le phénylglyci-nol, sous une forme optiquement active, dans un solvant choisi parmi l’acétate d’éthyle, les alcools, le dioxane et leurs mélanges, la séparation des deux sels diastéréoisomériques et la récupération de l’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoï-que à partir du sel correspondant. 2. Procédé selon la revendication 1, caractérisé en ce que ledit solvant est le dioxane. 3. Procédé selon l’une quelconque des revendications précédentes, caractérisé en ce que ladite amine est utilisée dans un rapport molaire amine/acide d’au moins 0,6/1. 4. Procédé selon les revendications 1 à 3, comprenant la mise en réaction, dans un solvant, du racémate d’acide 3-(carbamoylméthyl)-5-méthylhexanoïque avec une amine choisie parmi le (S)-(+)-phénylgly-cinol et la 1-(1-naphtyl)éthylamine, cette dernière étant sous une forme optiquement active ; la précipitation et l’élimination du précipité représenté par le sel de l’énantiomère (S)-(+) de l’acide ; et la récupération de l’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque à partir de la liqueur mère. 5. Procédé selon la revendication 4, caractérisé en ce que la réaction de salification se produit à une température comprise entre 25°C et la température de reflux du mélange de réaction. 6. Procédé selon l’une quelconque des revendications 4 ou 5, caractérisé en ce que ladite amine est choisie parmi la (R)-(+)-1-(1-naphtyl)éthylamine et le (S)-(+)-phénylglycinol. 7. Procédé selon l’une quelconque des revendications 4 à 6, caractérisé en ce que l’acide (R)-(-)-3-(car-bamoylméthyl)-5-méthylhexanoïque est récupéré à partir de la liqueur mère par extraction avec une solution aqueuse alcaline, et une acidification ultérieure de ladite solution alcaline. 8. Procédé selon la revendication 7, caractérisé en ce que l’acide (R)-(-)-3-(carbamoylméthyl)-5-méthyl-hexanoïque est isolé par une filtration après l’acidification. 9. Procédé selon les revendications 1 à 3, comprenant la mise en réaction du racémate d’acide 3-(carba-moylméthyl)-5-méthylhexanoïque avec du (R)-(-)-phénylglycinol dans un solvant ; la récupération du précipité consistant en le sel avec l’énantiomère (R)-(-) de l’acide ; et l’isolement de l’acide (R) -(-)-3-(carbamoylméthyl)-5-méthylhexanoïque. 10. Composé choisi dans le groupe consistant en le sel de (S)-(+)-phénylglycinol d’acide (S)-(+)-3-(carba-moylméthyl)-5-méthylhexanoïque ; le sel de (S) -(+)-phénylglycinol d’acide (R)-(-)-3-(carbamoyl-méthyl)-5-méthylhexanoïque ; le sel de (R)-(-)-phé-nylglycinol d’acide (S)-(+)-3-(carbamoylméthyl)-5-méthylhexanoïque et le sel de (R)-(-)-phénylglycinol d’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexa-noïque. 11. Composé choisi dans le groupe consistant en le sel de (R)-(+)-1-(1-naphtyl)éthylamine d’acide (S)-(+)-3-(carbamoylméthyl)-5-méthylhexanoïque ; le sel de (R)-(+)-1-(1-naphtyl)éthylamine d’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque ; le sel de (S)-(-)-1-(1-naphtyl)éthylamine d’acide (S)-(+)-3-(carbamoylméthyl)-5-méthylhexanoïque et le sel de (S)-(-)-1-(1-naphtyl)éthylamine d’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque. 12. Procédé de préparation de prégabaline (acide (S)-(+)-3-(aminométhyl)-5-méthylhexanoïque) comprenant : a) la mise en réaction d’un racémate d’acide 3-(carbamoylméthyl)-5-méthylhexanoïque dans un solvant avec une amine choisie parmi la 1-(1-naphtyl)éthylamine et le phénylglycinol, sous uneforme optiquement active, ledit solvant étant choisi parmi l’acétate d’éthyle, les alcools, le dioxane et leurs mélanges. b) la séparation des deux sels diastéréoisomé-riques et la récupération de l’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque à partir du sel correspondant ; c) la purification facultative de l’acide (R)-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque par cristallisation à partir d’un solvant organique ; d) la conversion de l’acide (R)-(-)-3-(carbamoyl-méthyl)-5-méthylhexanoïque en prégabaline. 13. Procédé selon la revendication 12, caractérisé en ce qu’à l’étape (d) l’acide (R)-(-)-3-(carbamoylmé-thyl)-5-méthylhexanoïque est converti en prégabaline par le biais d’une dégradation de Hoffmann.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • WO 0140159 A [0004] • JP 20030032863 B [0005] • EP 0828704 A [0006]

Claims (4)

ÜJÁRÁS (R)>{")~3~(KARBAM01L'M£TlL}-5-METIL'HEXÁNSAV, ÉS PRE0A3AÜN, ÉS SZINTÉZIS INTERMEDIEREK SyMliÍTÁSÁRá SZABADALMI ÎSÉRYPONTOKHANDLING (R)> {") ~ 3 ~ (KARBAM01L'M £ TlL) -5-METHYL'HEXA ACID, AND PRE0A3AÜN AND SYNTHESIS INTERMEDIATORS SYMBOLS 1. Epris előállására, ahol 32: eljárás a következő lépessel iaÄrsagzs* reagájtstuísk 3TXait3^ôiNme{i!î-5^iT>etiPexàRsaÿ iraosmátót -agy amteat, amely a kővetkezők közöl yáigszthatő ki; eijj*ámín és fenit-g lldaoi {más néven- S-arsiao^ááií-aíasoll, opfikailag: aktív ferfilbaR. agy öklőszsroen, amely si-acetáf, atóilfeki dioxáo ás eM keverékei közül viiszthaíő Éj; eíküiöníp k a.Éét: piaszíerseméf sók és a megfelelő sóből inyerp az (RH'/^a'karbanioll-mstiíi-S-rnetn-íföxánsavat1. For the generation of Epris, where 32: a procedure for the following step iaÄrsagzs * reaction stack 3TXait3 ^ ôiNme {i! Î-5 ^ iT> etiPexàRsaÿ iraosmató or amteat, which may be published by the following; eijj * amine and phenyl-ll the other oligonium salt, optically active as ferril. Brain Eclipse, which is a mixture of acetaphthyloxy, dioxane, and eM, each of which is Night; et al., pepper emulsion salts and the corresponding salt inyerp from (RH '/ N'-carbanol-methyl-S-methyl-phosphoric acid). 2. Az 1. igénypont szerinti eljárás, azzal jellemezve, hagy az említett oldószer dioxan. 3. : Az 1, vagy % igénypont szerit# átjárás, aæsal jsttemazvs, hogy: az említeti amint; legalább QM aminfsav möiarányban: alkalmazzuk.The process of claim 1, wherein said solvent is dioxane. 3. A 1 or% claim serine # cross-over, i.e., to mention amine; at least QM in amine acid ratio. 4. Az 1-3. IgénpmM bármelyike szeríri eljárás, am% a kővetkező lépéseket feramazza- egy ofboszerbep reeséiiairtk 3^ |pbswÉ«óí|^^iexáJsasf:raeeiiP egy amiertál, amely a következők közűi választható ki: {IH+IIÂÿ^^és 111-nail)^i^amin!:ahoi ezjtóbbi bárrnilyea spSkaüag aktív tormában lehet; kicsapjak es oííávoíltJuK a sav sbghpmepéaek sőjs által képviselt csapadékot; és az (R}11-31ka6ameiimnöt;l)'5-mei-hexänssyat :kinyegök azanyalügbot. 5. A 4, igénypont SzeÉi eljárás, azzal jellemezve, hegy a: sőképzésl (salification) reakció olyan hőmérsékleten megy végbe, amely a 25K3: és a réakcíökeverék visszsfolyatási (reflux) hőínérséklété közti tartományban vart. &amp; A A vagy 5. Igénpont szsűníi e|Mss, azzal jellemezve, hogy azemlett amim a következők közűi: választható ki: (RH+M--|1-maiij-efemin: és {oH+^ii-gloiÄ4. Referring to 1-3. Any of the following is a process that is% of the subsequent steps in the form of an enzyme, which is selected from the group consisting of: {IH + II 111 ^^ and 111-nail) ^ i <RTI ID = 0.0> amine: </RTI> which may be present in an active storm; precipitate and evaporate the precipitate represented by the acid sbghpmepéa; and (R} 11-31ka6ameiimnöt; l) '5-mei-hexänssyat: they are the same. 5. A method according to claim 4, wherein: the salification reaction is carried out at a temperature in the range of the reflux temperature of the 25K3: and the particulate mixture. &Amp; An A or A5 is a syllabus, characterized in that it is selected from the group consisting of: (RH + M-- | 1-Maiij efemin: and {oH + ^ ii-gloxy) 7. Az 1-3. igénypontok bármelyike szerinti eljárás. azzá jetlemeave, hogy az rRH-i'ö-p^amoif-meiJ-Ö^etihhexensevat az anyaiúgbol nyerjük ki extrahálással egy alkaiikus vizes oldattal és az emiatt aikaiikus oldat ezt követő megsavanyitásáva!. 8; A 7. igénypont Szerinti eljárás, azzal jeílsmezve, hop az (R51^r31karhamöíbmeií'5-me#-hexánsavst:szűps reyen izoláljuk smepaypyitás után. δ Az 1-3. igénypontok bármelyiké szsPri eljárás, amely a kővetkező lépéseket tartalmazza' reagáltunk 3-;karbamoikneíií}-5-metMékánsav rácsmátot (R)1-)kténii-gíiciriö!iál egy oidészerpén; kinyerjük a sáv enantisménévsl bíró sóját tárísimazé csapadékot;: és izoláljuk az 10. tfegyuiet, amely a következők közül yáiasztifató ki: (S)1^i#|ksrbamoil-metii)-S-meíil-f:exánsev {$)-j*}^h|>glctnol sójo; (R}<-{-^3«ikarbamöihmetii)-5--n^st!l'-iiexär5S3v ($}-(*Henll-gllcinoi sója: (S/lr-j-ő-íkarbamoli-metiil-S-mehl-hexánsav (RHI-femi-l&amp;lnoí: sója; és í i-ÿ-3-p®rfaamo H-metl I}-5-rrrotä- hökánsov (R)H-fenll-gkanoi sója. '11. hegyiét amely s következők: kézi vâlàszinatè ki: p|-^|4^1^al|-etii'aröiít sója; (R|^^3-i;kapmoflwat)^mÄte#nsav (R)_(+>-1 -( 1 -naíütj-etií-amín sója; sója; es 1¾ amely eljárás a következő lépéseket jeeplstpk S'lk^a^eiS'meíiSl-S'metÍkhexáesev rxemátof egy aminnal;,. amely a következők; kézi választható kit ei-amiá ési iehlbgiicsrsel fnas hever? &amp;3minö-2^nil-et8neS}y optikailag! aktív tormába·'!, egy Äszerben, amely ei^cetáí. alkoholok, díoxae és ezek keverek® közül választható ki; elkeilhtpk: a köt öiásztetéomer sőt; és a. megfelelő: sóból; kinyerjek. az (Ri-PrS^karbameil'metilii^^stil-hex^esevat; ktváaí:esetbéft tisztipk az PH'i'^ikarbémolí'meliJ^-ffletil-bexáessvaí kristályosítás révértegy szerves oldószerből; és az! |R}-|-Í4^(kS:rbamoil'me®}-í^meifNbe5Sá:nsavaí átaíákipk pregaha!iaf!:áv 13. A12.:ípnyporít szerint! eljárás, azzal; jattemazvé, hegy a b|; lépésben az Hoftmarm ieböntässsgitsegivef slakajuRM psgaöatinaá7. The method of any one of claims 1 to 3. mentioning that rRH-α-p-amo-phenoxy-ethylhexene is recovered from the mother liquor by extraction with an alkaline aqueous solution and subsequent acidification of the alkali solution. 8; Process according to claim 7, characterized in that hop is (R51 ^ r31karhamöbmei'5-me # -hexanoic acid: narrowed down after smepay retention.) The method of any one of claims 1-3, comprising the steps of "reacting" with a third step. carbamycinyl} -5-methanoic acid lattice (R) 1-) cyanogen glycol moiety on a diode; recovering the precipitate of the enantiomeric salt of the band; and isolating the tertiary compound 10 which is selected from the group consisting of: (S) 1 [mu] rbamoylmethyl) -S-methyl-ex: exanthene {$) - j * } ^ h |> glctnol salt; (R) <- {- {3 "carbamoylmethyl) -5 - [(1S) - (3-fluorophenyl) -5 (3-fluorophenyl) -phenyl] - (* Henllglcino salt: (S / lr-γ-carbamol-methyl-S-) Mehl-hexanoic acid (RHI-phemi-l &amp;amp;ln;salt; and ÿ-3-pyrroman-H-methyl) -5-pyrrothiocyano (R) H-phenylganoo salt. which is as follows: manual synthesis: p | - ^ | 4 ^ 1 ^ al | -ethylin (R | ^ ^ 3-i; kapmoflwat) ^ matt # n ((R) _ (+> - 1 - (1-sodium-ethylamine salt; salt; and 1? Which process comprises the following steps jeeplstpk S'lk ^ a-niS'meiIl-S'met-hexhexa-rxemate with an amine;, which is the following; iehlbgiicsrsel fnas hns? &amp; 3minö-2 ^ nil-et8neS} y in an optically active horseradish · 'in an appetite that can be selected from non-acetal alcohols, oxalate, and mixtures thereof, elkeilhtpk; suitable: from salt, recover from (R1-PrS1-carbamoylmethyl) phenyl-hexahydroxypyridone; and the? | R} - | -? 4 (kS: rbamoil'me®) -? procedure with it; jattemazve, mountain b | in step 2, the Hoftmarm antispasmodic gate is a slakajuRM psgaöatinaá
HUE07766518A 2006-07-04 2007-06-06 Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates HUE026917T2 (en)

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